Lipoprotein(a) [Lp(a)] is a serum lipoprotein consisting of one molecule of apolipoprotein B-100 (apoB) and one molecule of apolipoprotein(a) [apo(a)], which are bonded through a single disulfide bond; and a cholesterol-rich low-density lipoprotein (LDL) particle, (non-patent document 1), and found only in humans, primates and hedgehog. The apo(a) is a homologue of plasminogen (non-patent document 2), containing 10 different types (kringle-4 types 1 through 10) of plasminogen kringle-4 like repeats as well as regions homologous to the kringle-5 and inactive protease regions (non-patent document 3). Lp(a) has been considered as an independent cardiovascular risk factor and several studies have shown the association between plasma Lp(a) levels and cardiovascular disease (CVD)/coronary heart disease (CHD). Elevated Lp(a) levels promote atherosclerosis via Lp(a)-derived cholesterol entrapment in intima; via inflammatory cell recruitment; and/or via the binding of pro-inflammatory-oxidized phospholipids (non-patent document 4). Lipid lowering agents have little effect on plasma Lp(a) level (non-patent document 5). Although it has been reported that administration of niacin or estrogen may reduce the Lp(a) levels, there is no specific agent for the reduction of plasma Lp(a) (non-patent document 6-8).
Non-patent document 9 discloses a measurement method of Lp(a) which is not influenced by the polymorphism of apo(a).
While vaccine is often used for the prophylaxis or treatment of diseases caused by exogeneous factors, such as infections and the like, even for the diseases caused by endogenous aggravation factors such as Alzheimer's disease, hypertension and the like, vaccine therapy has been tried, which includes administering the aggravation factors, epitopes contained in the aggravation factors, or expression vectors encoding them to patients to induce the antibody to the aggravation factor in the body of patients, thereby neutralizing the function of the aggravation factor and mitigating the symptoms of the target disease (non-patent documents 10-12). Plasmid DNA vaccination is one of the tools to induce both humoral and cellular immune responses, without co-treatment with adjuvant, because in the case of plasmid DNA, unmethylated CpG motifs expressed with a plasmid unmethylated CpG motifs expressed with a plasmid backbone have been considered to be “built-in” adjuvants, owing to their ability to activate the innate immune system by means of TLR9 (non-patent document 13). In addition, recent accumulating evidence suggests that the double-stranded structure of DNA, independently of CpG motifs, possesses immunomodulatory effects when introduced into the cytosol or its homeostatic clearance is hampered.
However, when the aggravation factor is endogenous, the immune tolerance to the factor has generally been established since the factor is the patient's own component. Therefore, it is difficult to efficiently induce an antibody to the factor in the body of the patient even when these endogenous aggravation factors or partial peptides thereof are directly administered to the patient. As such, some technical idea is necessary to have the patient's immune system recognize these self antigens, thereby inducing the production of the antibody.
Hepatitis B virus core (HBc) antigen protein constitutes spherical core particles by self assembly. The core particles have very high immunogenicity. When a fusion polypeptide obtained by inserting a desired epitope into a particular site of the HBc antigen protein, or connecting a desired epitope to the terminus of the HBc antigen protein is used, the epitope is presented on the surface of the particles formed by self-assembly. Using the fusion polypeptide, the inserted epitope is easily recognized by the immune system, and the production of the antibody that recognizes the epitope can be efficiently induced. Therefore, utilizing the HBc antigen protein as a platform of vaccine, attempts have been made to induce production of the antibody to an antigen difficult to be recognized by the immune system (non-patent document 14, non-patent document 15).
Patent document 1 discloses particles composed of a chimeric HBc antigen protein containing an foreign amino acid sequence having an epitope, wherein the foreign amino acid sequence is inserted into the amino acid residues 80-81 of the HBc antigen.
Non-patent document 16 describes that intramuscular immunization with a DNA vaccine encoding ISS and an HBc antigen inserted with a CETP epitope consisting of 26 amino acids inhibited atherosclerosis in rabbit atherosclerosis model.
However, even if production of an antibody to an endogenous aggravation factor can be induced, when cellular immunity to the factor is simultaneously induced, side effects are caused by the autoimmune reaction. Therefore, it is necessary to efficiently induce the production of an antibody to the endogenous aggravation factor while suppressing the induction of self-reactive T cells.
Under the above situation, a DNA vaccine showing totally satisfying effectiveness to arteriosclerosis has not been developed yet.